ABSTRACT Influenza viruses cause up to 500,000 deaths around the globe annually. An ideal influenza vaccine must have two essential attributes: one, it should be capable of inducing broadly cross-reactive antibodies that can neutralize diverse influenza virus strains; and two, it must induce long-lived antibody responses to maintain protective immunity for extended periods. Licensed seasonal influenza virus vaccines do neither ? the antibody response is of limited breadth and vaccine-induced immunity appears to be of short duration. Early work has established that induction of hemagglutinin (HA)-specific antibodies is essential and sufficient for protection. Despite the extensive efforts and resources that have been deployed to fight influenza over the past eight decades, it remains a major public health threat. There are major gaps in our understanding of memory B cell (MBC) responses to influenza virus vaccination in humans: (1) does influenza vaccination induce functionally and clonally distinct subsets of MBCs? (2) do all of the induced MBCs become part of the long-term memory pool? 3) do all MBC subsets possess the same breadth in terms of the influenza epitopes targeted by their corresponding B cell receptors (BCRs)? 4) what is the fate of the different MBC subsets upon re-exposure to antigen? 5) are some of the induced MBCs poised more for effector function (differentiation into antibody secreting cells or plasmablasts) than for proliferation and self-renewal? Tackling these gaps will allow us to discern which MBC subset is associated more with longevity and breadth of the induced antibody response. In our studies, we will address these outstanding questions through detailed phenotypic, functional and transcriptional analysis of influenza vaccination-induced HA-binding MBCs. Our preliminary data show that there are at least two distinct subsets of vaccine-induced MBCs that differ in the kinetics of their appearance in blood, isotype distribution, and differentiation potential. Additionally, our transcriptional analyses reveal differential expression of key transcription factors, such as TCF-1 that are associated broadly with isotype- switching and self-renewal capacity. Understanding the heterogeneity of influenza vaccines-induced MBCs responses is unarguably a major public health need and our findings will provide a basis for dissecting such heterogeneity.